The pathogenic roles of heparan sulfate deficiency in hereditary multiple exostoses

Abstract

Heparan sulfate (HS) is an essential component of cell surface and matrix proteoglycans (HS-PGs) that include syndecans and perlecan. Because of their unique structural features, the HS chains are able to specifically interact with signaling proteins -including bone morphogenetic proteins (BMPs)- via their HS-binding domain, regulating protein availability, distribution and action on target cells. Hereditary Multiple Exostoses (HME) is a rare pediatric disorder linked to germline heterozygous loss-of-function mutations in EXT1 or EXT2 that encode Golgi-resident glycosyltransferases responsible for HS synthesis, resulting in a systemic HS deficiency. HME is characterized by cartilaginous/bony tumors -called osteochondromas or exostoses- that form within perichondrium in long bones, ribs and other elements. This review examines most recent studies in HME, framing them in the context of classic studies. New findings show that the spectrum of EXT mutations is larger than previously realized and the clinical complications of HME extend beyond the skeleton. Osteochondroma development requires a somatic "second hit" that would complement the germline EXT mutation to further decrease HS production and/levels at perichondrial sites of osteochondroma induction. Cellular studies have shown that the steep decreases in local HS levels: derange the normal homeostatic signaling pathways keeping perichondrium mesenchymal; cause excessive BMP signaling; and provoke ectopic chondrogenesis and osteochondroma formation. Data from HME mouse models have revealed that systemic treatment with a BMP signaling antagonist markedly reduces osteochondroma formation. In sum, recent studies have provided major new insights into the molecular and cellular pathogenesis of HME and the roles played by HS deficiency. These new insights have led to the first ever proof-of-principle demonstration that osteochondroma formation is a druggable process, paving the way toward the creation of a clinically-relevant treatment.

Bone development and remodeling in metabolic disorders

“…This will lead to a local lack of heparan sulfate and an impaired regulation of bone growth, giving rise to osteochondromas . The role of heparan sulfate in the disease has been recently reviewed by Maurizio Pacifici . The decrease in exostosin and heparan sulfate levels caused by the second hit (the somatic mutation in the WT allele of the EXT gene with a germline mutation in the other allele) causes a decrease in signaling molecules such as fibroblast growth factor (FGF), MAPK/ERK Kinase (MEK), extracellular‐signal‐regulated kinase (ERK), Noggin, and Gremlin, and an increase of bone morphogenetic protein (BMP) and hedgehog (Hh) signaling and of heparanase, which are involved in the abnormal growing of bone.…”

Heparan sulfate co-immobilized with cRGD ligands and BMP2 on biomimetic platforms promotes BMP2-mediated osteogenic differentiation

“…The effect of HS on BMP2 signaling is the subject of scientific debate [13,[29][30][31][32][33]. It was previously shown that HS inhibits BMP2 bioactivity [31][32][33][34][35] as it does for different GFs [36].…”

Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

“…Altered synthesis of specific GAG species has also been observed in skeletal disorders such as in hereditary multiple exostosis with a specific defect in HS synthesis . In EXTL3 ‐deficient cells, reduced HS synthesis coupled to increased CS and DS synthesis have been observed .…”